Multiple forms of spontaneous respiratory neuroplasticity occur at spinal and brainstem levels in adult rats after lesions to the cervical spinal cord. The goal of this proposal is to enhance naturally occurring processes that can lead to partial improvement of phrenic motoneuron (PhMN) functions that were initially lost or modified after high cervical spinal cord injury (SCI) and to define underlying changes in the neural substrate. Current understanding of neuroplasticity in the phrenic motor system (PhMtrS) derives from studies of spinal hemilesions made above the phrenic nucleus (e.g., at C2). That injury abolishes descending inspiratory drive to ipsilateral PhMNs and renders the corresponding ipsilateral diaphragm (ipsiDIA) hemiparetic. We and others have recently described spontaneously emerging changes in PhMN function after C2 HMx - two of which are emphasized in the proposal. One entails a partial spontaneous recovery of ipsilateral diaphragm activity. The second involves a specific change in contralateral PhMN responses to elevated respiratory drive (hypercapnia). Aim 1 will test the hypothesis that spontaneous, partial recovery of ipsiPhMN function following a C2 HMx entails neural circuit remodeling via the recruitment of interneurons. Aim 2 will test the hypothesis that stimulation of axonal growth by blockade of the Nogo receptor (NgR), using the NgR antagonist, NEP1-40, will enhance spontaneously evolving ipsilateral PhMN functional recovery and possibly amplify the novel circuit to be defined in Aim 1, as well as contribute to modification of contralateral PhMN neuroplastic responses to respiratory challenge. The third Aim will test the hypothesis that introduction of a novel short propriospinal circuit via neural tissue transplantation can modify, alone or in combination with NEP1-40 delivery, ipsi- and contralateral PhMN neuroplastic responses following C2 HMx injury. We also will assess whether engraftment and therapeutic efficacy of FSC tissue can be complemented by NgR blockade. A multidisciplinary approach will be used involving transneuronal tracing, quantitative neurophysiological indices, and an innovative approach for obtaining repeated measures of breathing in freely-behaving rats. These aims identify with the long-range hypothesis that segmental gray matter repair and neural circuit remodeling provide an effective complement or alternative to long-tract regeneration via enhancement or modification of post-injury neuroplastic events. [unreadable] [unreadable] [unreadable]